This application is a 371 of PCT/GB99/02924 filed Sep. 3, 1999.
The present invention relates to 4-quinolderivnatives and their use in therapy. In particular, the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial. The invention relates in particular to adenosine receptors and particularly adenosine A2A receptors, and to the treatment of movement disorders such as Parkinson""s disease.
Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson""s disease, Alzheimer""s disease, Huntington""s chorea and Wilson""s disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
There are four classic symptoms of Parkinson""s disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson""s disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson""s disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson""s disease are manifested.
Current strategies for the treatment of Parkinson""s disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g. Deprenyl(copyright)), dopamine receptor agonists (e.g. bromocriptine and apomorphine) and anticholinergics (e.g. benztrophine, orphenadrine). Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when xe2x80x9con-offxe2x80x9d symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients. Despite new drug approvals, there is still a medical need in terms of improved therapies for movement disorders, especially Parkinson""s disease. In particular, effective treatments requiring less frequent dosing, effective treatments which are associated with less severe side-effects, and effective treatments which control or reverse the underlying neurodegenerative disorder, are required.
Blockade of A2 adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson""s disease (Richardson, P. J. el al., Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65). The potential utility of adenosine A2A receptor antagonists in the treatment of movement disorders such as Parkinson""s Disease has recently been reviewed (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320).
Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407-422). This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. Exp. Opin. Ther. Patents 1995, 5,547-558).
Adenosine receptors represent a subclass (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A1, A2A, A2B (of high and low affinity) and A3 (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156). The adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128).
The design of P1 receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerafive disorders, such as Parkinson""s disease (Williams, M. and Bumstock, G. Purinergic Approaches Exp. Ther. (1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)
The pharmacology of adenosine A2A receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364-372). One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A2 adenosine receptors is the evidence of a functional link between adenosine A2A receptors to dopamine D2 receptors in the CNS. Some of the early studies (e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7238-41) have been summarised in two more recent articles (Fuxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., [Proc. Int. Symp.], 5th (1995), 499-507. Editors: Belardinelli, Luiz; Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Trends Neurosci. 1997, 20, 482-487).
As a result of these investigations into the functional role of adenosine A2A receptors in the CNS, especially in vivo studies linking A2 receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991, 130, 162-4; Mandhane, S. N. et al., Eur. J. Pharmacol. 1997, 328, 135-141) investigations have been made into agents which selectively bind to adenosine A2A receptors as potentially effective treatments for Parkinson""s disease.
While many of the potential drugs for treatment of Parkinson""s disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A2A antagonist therapy is that the underlying neurodegenerative disorder is also treated. The neuroprotective effect of adenosine A2A antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N. Y. Acad. Sci. 1997, 825(Neuroprotective Agents), 30-48).
Xanthine derivatives have been disclosed as adenosine A2 receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A2 receptors, such as Parkinson""s disease (see, for example, EP-A-565377).
One prominent xanthine-derived adenosine A2A selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323, 141-144).
Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A1 and A2A receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in Parkinson""s disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W. J. Pharm. Pharmacol. 1994, 46, 515-517).
KF 17837 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] is a selective adenosine A2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine. Moreover, KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A2A receptor antagonist and that the dopaninergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268). The structure activity relationship (SAR) of KF 17837 has been published (Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352). Recent data has also been provided on the A2A receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr. 1997, 23, 119.14; and Kanda, T. et al., Ann. Neurol. 1998, 43(4), 507-513).
New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective A2A Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164-71). SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70) and has been followed up by a later series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998, 41(12), 2126-2133).
The foregoing discussion indicates that a potentially effective treatment for movement disorders in humans would comprise agents which act as antagonists at adenosine A2A receptors.
It has now been found that 4-quinolinylmethanol derivatives, which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (P1) receptors, and in particular at the adenosine A2A receptor. Such compounds may therefore be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias. These may include Parkinson""s disease, Alzheimer""s disease, spasticity, Huntingdon""s chorea and Wilson""s disease.
According to the present invention there is provided use of a compound of formula (I): 
wherein:
R1 is hydrogen or alkyl;
R2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N;
R3 and R4 are independently selected from hydrogen, alky, aryl, COR13, CO2R13, CONR13R14, CONR13NR14R15, SO2R13, SO2NR13R14, SO2NR13NR14R15 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, or together may form a 3, 4, 5, 6, 7 or 8 membered saturated, partially unsaturated or aromatic heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N;
or R1 and R4 together may form a 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring optionally containing an additional heteroatom selected from O, S and N;
or R2 and R3 together may form a 4, 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N;
R5 and R6 are independently selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, or together may form a 3, 4, 5, 6 or 7 membered saturated or partially unsaturated carbocyclic ring or a 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from O, S and N;
or R3 and R5 together may form a 4, 5, 6 or 7 membered unbridged, saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N;
wherein said carbocyclic or said heterocyclic ring when partially unsaturated or aromatic may be fused to an aryl ring;
with the proviso that where R3 and R5 together form a ring, then R3 and R4 do not also form a ring;
R7, R8, R9, R10, R11 and R12 are independently selected from hydrogen, alkyl, aryl, 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, hydroxy, halogen, nitro, cyano, alkoxy, aryloxy, COR13, OCOR13, CO2R13, SR13, SOR13, SO2R13, SO2NR13R14, CONR13R14, CONR13NR14R15, OCONR13R14, NR13R14, NR13COR14, NR15CONR13R14, NR13CO2R14, NR13SO2R14, CR13NOR14, NR13CONR14NR15R16, NR13NR14CO2R15, NR13NR14CONR15R16, NR13NR14COR15, NR13NR14SO2R15, SO2NR13NR14R15, NR13SO2NR14NR15R16 and NR13SO2NR14R15, wherein R13, R14, R15 and R16 are independently selected from hydrogen, alkyl and aryl,
or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A2A receptors, may be beneficial.
As used herein, the term xe2x80x9calkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to C10, more preferably C5, C6 or C7. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, more preferably methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl or t-butyl.
As used herein, the term xe2x80x9carylxe2x80x9d means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more heteroatom, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pryazolyl, triazolyl, imidazolyl or pyrimidinyl.
The alkyl and aryl groups may be substituted or unsubstituted. Where R1 and R4; or R2 and R3; or R3 and R4; or R3 and R5; or R5 and R6 together form a ring, the ring may be substituted or unsubstituted.
Where any group is substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include: carbon-containing groups such as
alkyl,
aryl,
arylalkyl (e.g. substituted and unsubstituted phenyl, substituted
and unsubstituted benzyl);
halogen atoms and halogen-containing groups such as
haloalkyl (e.g. trifluoromethyl);
oxygen-containing groups such as
alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl),
ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl),
aldehydes (e.g. carboxaldehyde),
ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl),
acids (e.g. carboxy, carboxyalkyl),
acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl),
amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonyl, arylaminocarbonyl),
carbamates (e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy)
and ureas (e.g. mono- or di-alkylaminocarbonylamino or arylaminocarbonylamino);
nitrogen-containing groups such as
amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl),
azides,
nitriles (e.g. cyano, cyanoalkyl),
nitro;
sulfur-containing groups such as
thiols, thioethers, sulfoxides and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);
and heterocyclic groups containing one or more, preferably one, heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94 and xe2x80x9calkoylxe2x80x9d means alkyl-COxe2x80x94. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by one or more alkyl groups.
As used herein, the term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical.
As used herein the term xe2x80x9cprodrugxe2x80x9d means any pharmaceutically acceptable prodrug of the compound of formula (I).
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobrornic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, sulfuric and methanesulfonic acids, and most particularly preferred is the hydrochloric salt. Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
As used herein, the term xe2x80x9csaturated heterocyclic ringxe2x80x9d means a heterocyclic ring wherein the bonds between the atoms forming the ring are single bonds. Examples of such saturated heterocyclic rings include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, hexahydroazepinyl, heptamethyleneiminyl, oxiranyl, oxetanyl tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyran, piperazinyl, morpholinyl, dioxanyl and thiomorpholinyl.
As used herein, the term xe2x80x9cpartially unsaturated heterocyclic ringxe2x80x9d means a heterocyclic ring wherein one or more of the bonds between the atoms forming the ring are unsaturated bonds and wherein the ring is non-aromatic in character. Examples of such partially unsaturated rings include 3-pyrrolinyl, imidazolinyl, oxazolinyl, thiazolinyl, pyrrazolinyl, dihydropyranyl, pyranyl, dihydropyridinyl and tetrahydropyridinyl.
As used herein, the term xe2x80x9ccarbocyclic ringxe2x80x9d means a ring wherein the atoms forming the ring are carbon atoms and wherein the ring is either (a) a saturated ring in which the bonds between the ring atoms are single bonds (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, or a bicyclic ring such as norbomanyl); or (b) a partially unsaturated ring wherein one or more of the bonds between the ring atoms are unsaturated bonds and wherein the ring is non-aromatic in character (such as cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cycloheptadienyl); or (c) an aromatic ring (such as phenyl).
As used herein, the term xe2x80x9cunbridgedxe2x80x9d refers to a ring or ring system which is not bridged; the term xe2x80x9cbridgedxe2x80x9d referring to a ring system in which two or more rings share non-adjacent atoms to form a multicyclic ring system. Examples of a bridged ring system include adamantane, norbomane and 5-ethenyl-1-azabicyclo[2.2.2]octane.
As used herein, the term xe2x80x9cfusedxe2x80x9d refers to a ring system in which two rings or ring systems share only adjacent ring atoms. Examples of a fused ring system include naphthalene, quinoline, indan and benzofuran.
Where any of R2 to R12 are selected from 4, 5, 6, 7 or 8 membered heterocyclic rings containing a plurality of heteroatoms selected from O, S and N, the heteroatoms may be the same or different.
Where R3 and R4; or R1 and R4; or R2 and R3; or R5 and R; or R3 and R5 together form a heterocyclic ring containing a plurality of heteroatoms selected from O, S and N, the heteroatoms may be the same or different.
Where R3 and R4 together form a 3 membered heterocyclic ring, it is preferred that said ring is saturated and contains no more than one heteroatom.
In a first embodiment of the invention, R1 is hydrogen or alkyl; R2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N; and R3 and R4 are independently selected from hydrogen, alkyl, aryl, COR13, CO2R13, CONR13R14, CONR13NR14R15, SO2R13, SO2NR13R14, SO2NR13NR14R15 and 4,5,6,7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, wherein said heterocyclic ring(s) when partially unsaturated may be fused to an aryl ring.
In a second embodiment of the invention, R1 is hydrogen or alkyl; R2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N; and R3 and R4 together form a 3, 4, 5, 6, 7 or 8 membered saturated, partially unsaturated or aromatic heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, wherein said heterocyclic ring(s) when partially unsaturated or aromatic may be fused to an aryl ring.
In a third embodiment of the invention, R1 and R4 together form a 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring optionally containing an additional heteroatom selected from O, S and N; R2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N; and R3 is selected from hydrogen, alkyl, aryl, COR13, CO2R13, CONR13R14, CONR13NR14R15, SO2R13, SO2NR13R14, SO2NR13NR14R15 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, wherein said heterocyclic ring(s) when partially unsaturated may be fused to an aryl ring.
In a fourth embodiment of the invention, R1 is hydrogen or alkyl; R2 and R3 together form a 4, 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N; and R4 is selected from hydrogen, alkyl, aryl, COR13, CO2R13, CONR13R14, CONR13NR14R15, SO2R13, SO2NR13R14, SO2NR13NR14R15 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, wherein said heterocyclic ring(s) when partially unsaturated may be fused to an aryl ring.
In each of the first, second, third and fourth embodiments set out above, R5 and R6 are independently selected from hydrogen, alkyl (including cycloalkyl, ara-alkyl and heteroara-alkyl), aryl (including heteroaryl) and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, or together may form a 3, 4, 5, 6 or 7 membered saturated or partially unsaturated carbocyclic ring or a 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from O, S and N, wherein said carbocyclic ring or said heterocyclic ring when partially unsaturated may be fused to an aryl ring.
In a fifth embodiment of the invention, R1 is hydrogen or alkyl; R2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N; R4 is selected from hydrogen, alkyl, aryl, COR13, CO2R13, CONR13R14, CONR13NR14R15, SO2R13, SO2NR13R14, SO2NR13NR14R15 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N; R6 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N; and R3 and R5 together form a 4, 5, 6 or 7 membered unbridged, saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, wherein said heterocyclic ring when partially unsaturated may be fused to an aryl ring.
In each of the first, second, third, fourth and fifth embodiments set out above, R7, R8, R9, R10, R11 and R12 are independently selected from hydrogen, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl), ara-alkyl and heteroara-alkyl), aryl (including heteroaryl), 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, hydroxy, halogen, nitro, cyano, alkoxy, aryloxy, COR13, OCOR13, CO2R13, SR13, SOR13, SO2R13, SO2NR13R14, CONR13R14, CONR13NR14R15, OCONR13R14, NR13R14, NR13COR14, NR15CONR13R14, NR13CO2R14, NR13SO2R14, CR13NOR14, NR13CONR14NR15R16, NR13NR14CO2R15, NR13NR14CONR15R16, NR13NR14COR15, NR13NR14SO2R15, SO2NR13NR14R15, NR13SO2NR14NR15R16 and NR13SO2NR14R15, wherein R13, R14, R15, and R16 are independently selected from hydrogen, alkyl and aryl.
In the compounds of formula (I), where any of R2, R3, R4, R5 and R6 are selected from 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, said heterocyclic ring is preferably unbridged; preferably monocyclic; and is preferably a 5 or 6 membered ring. Where said heterocyclic ring is partially unsaturated and is fused to an aryl ring, said aryl ring is preferably phenyl.
In the compounds of formula (I), where any of R7 to R12 are selected from 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, said heterocyclic ring is preferably unbridged; preferably monocyclic; and is preferably a 5 or 6 membered ring.
In the compounds of formula (I), where R1 and R4; or R2 and R3; or R3 and R4; or R5 and R6 together form a ring, said ring is preferably unbridged; preferably monocyclic; and is preferably a 4, 5 or 6 membered ring, preferably a 5 or 6 membered ring. Where any of said rings is partially unsaturated and is fused to an aryl ring, said aryl ring is preferably phenyl.
Preferably, the compounds of formula (I) are selected from compounds in which R1 is hydrogen or methyl or from compounds in which R1 forms a 5 or 6 membered heterocyclic ring with R4.
Preferably, the compounds of formula (I) are selected from compounds in which R2 is hydrogen or from compounds in which R2 forms a 4, 5 or 6 membered, preferably a 4 membered, heterocyclic ring with R3.
R3 and R4 are independently selected from hydrogen, alkyl (including cycloalkyl, ara-alkyl and heteroara-alkyl), aryl (including heteroaryl) COR13, CO2R13, CONR13R14, CONR13NR14R15, SO2R13, SO2NR13R14, SO2NR13NR14R15 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, or together may form a 3, 4, 5, 6, 7 or 8 membered saturated, partially unsaturated or aromatic heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, wherein said heterocyclic ring when partially unsaturated or aromatic may be fused to an aryl ring.
Preferably, the compounds of formula (I) are selected from compounds in which R3 is hydrogen, alkyl (preferably methyl, benzyl cyclobutyl or isobutyl), aryl (preferably phenyl), COR13 (preferably wherein R13 is alllyl, preferably methyl) or CO2R13 (preferably where R13 is alkyl, preferably t-butyl), or from compounds in which R3 forms a 5 or 6 membered ring with R4 or from compounds in which R3 forms a 5 or 6 membered heterocyclic ring with R5 or from compounds in which R3 forms a 4, 5 or 6 membered heterocyclic ring with R2.
Preferably, the compounds of formula (I) are selected from compounds in which R4 is hydrogen, alkyl (preferably methyl, cyclobutyl or isobutyl, or ara-alkyl (preferably benzyl or phenylethyl)), aryl (preferably phenyl), COR13 (preferably wherein R13 is alkyl, preferably methyl) or CO2R13 (preferably where R13 is allyl, preferably t-butyl), or from compounds in which R4 forms a 5 or 6 membered heterocyclic ring with R3 or from compounds in which R4 forms a 5 or 6 membered heterocyclic ring with R1.
Preferably, the compounds of formula (I) are selected from compounds in which R5 is hydrogen, alkyl (preferably methyl, secondary butyl or isobutyl or ara-alkyl (preferably benzyl)) or from compounds in which R5 forms a 5 or 6 membered heterocyclic ring with R3.
Preferably, the compounds of formula (I) are selected from compounds in which R6 is hydrogen or alkyl (preferably methyl, secondary butyl or isobutyl or ara-alkyl (preferably benzyl)).
In an embodiment of the invention, where any of R4 to R9 are independently selected from NR13COR14, then R13 of the or each NR13COR14 group is hydrogen.
It is preferred that at least one of R7 to R12 is a group other than hydrogen.
In an embodiment of the invention, the compounds of formula (I) are selected from compounds other than compounds in which both R7 and R12 are halo-alkyl (including trifluoromethyl). In a further embodiment of the invention, R7 and/or R12 are selected from hydrogen, hydroxy, alkyl (preferably unsubstituted alkyl, preferably methyl), alkoxy (preferably methoxy) and NR13R14 (preferably where R13 and R14 are selected from hydrogen and alkyl (preferably methyl)).
In a further embodiment, R7 is selected from hydroxy, NR13R14 (preferably where R13 and R14 are selected from hydrogen and alkyl (preferably methyl), and preferably hydrogen) and alkoxy (preferably methoxy).
In a further embodiment, R12 is selected from hydrogen and alkyl (preferably methyl).
Preferably, the compounds of formula (I) are selected from compounds in which R8, R9 R10 and/or R11 is hydrogen.
In an embodiment of the invention, the compounds of formula (I) are selected from (1R,8aS)-1,5,6,7,8,8a-hexahydro-1-(2,8-bis(trifluoromethyl)-4-quinolinyl)-3H-oxazolo[3,4-a]pyridine, (11R, 2xe2x80x2S)-xcex1-(1-methyl-2-piperidinyl)-2,8-bis(trifluoromethyl)4-quinolinemethanol, (xe2x88x92)-(11R, 2xe2x80x2S)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol, (xe2x88x92)-(11R, 2xe2x80x2R)-xcex1-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol and (11S*, 2xe2x80x2R*)-xcex1-(2-Piperidinyl)-2-trifluoromethyl-4-quinolinemethanol.
Where chiral, the compounds of formula (I) may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.
Where R2 is H or alkyl, it is preferred that the compounds of formula (I) are selected from compounds in which the stereochemical configuration at the carbon atom bound to the 4-position of the quinoline ring is R.
According to a further aspect of the present invention there is provided a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial, the method comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
The disorder may be caused by the hyperfunctioning of the purine receptors.
According to a further aspect of the present invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of movement disorders in a subject.
According to a further aspect of the invention there is provided a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
According to a further aspect of the invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.
According to a further aspect of the invention there is provided a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
The medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.
According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I) wherein R1 and R4 together may form a 5, 6 or 7 saturated, partially unsaturated or aromatic membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, or a pharmaceutically acceptable salt or prodrug thereof.
According to a further aspect of the invention there is provided for use in therapy a compound of formula (I) wherein R2 is H or alkyl and wherein the stereochemical configuration at the carbon atom bound to the 4-position of the quinoline ring is R, or a pharmaceutically acceptable salt or prodrug thereof.
The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
The disorders of particular interest are Parkinson""s disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson""s disease (punch-drunk syndrome).
Other movement disorders in which the therapy may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive allidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, Alzheimer""s disease or other disorders of the basal ganglia which result in abnormal movement or posture.
A further example of a disorder in which the blocking of purine receptors may be beneficial is depression.
The compound of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
The present invention may also be effective in treating Parkinson""s with on-off phenomena; Parkinson""s with freezing (end of dose deterioration); and Parkinson""s with prominent dyskinesias.
According to a further aspect of the invention, there is provided a compound of formula (I) wherein R1 and R4 together may form a 5, 6 or 7 saturated, partially unsaturated or aromatic membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, or a pharmaceutically acceptable salt or prodrug thereof.
According to a further aspect of the invention there is provided a compound of formula (I) wherein R2 is H or alkyl and wherein the stereochemical configuration at the carbon atom bound to the 4-position of the quinoline ring is R, or a pharmaceutically acceptable salt or prodrug thereof.
According to another aspect of the invention there is provided a method of preparing the novel compounds of formula (I). Compounds of formula (I) may be prepared by conventional synthetic methods such as those illustrated in Reaction Schemes 1-5. 
Compounds of formula (I) where R1 is an alkyl group are prepared from compounds of formula (2) (Reaction Scheme 1) by standard methods such as alkylation with an alkyl halide in the presence of a suitable base such as NaH.
Compounds of formula (2) where R4 is an alkyl group are prepared from compounds of formula (3) in two steps by standard methods such as removal of the protecting group using, for example TFA, followed by reductive alkylation of the resulting amine using an appropriate aldehyde or ketone in the presence of a suitable reducing agent such as NaCNBH3. Compounds of formula (2) where R4 is hydrogen are prepared from compounds of formula (3) by deprotection as described above.
Compounds of formula (3) where R3 is an alkyl group are prepared from compounds of formula (3) where R3 is hydrogen by standard methods such as alkylation using an appropriate alkyl halide in the presence of a suitable base such as NaH.
Compounds of formula (3) where R2 is hydrogen are prepared from compounds of formula (4) by reaction with a suitable reducing agent such as NaBH4.
Compounds of formula (3) where R2 is an alkyl or aryl group are prepared from compounds of formula (4) by reaction with an appropriate nucleophile such as a Grignard reagent or an alkyl or aryl lithium reagent.
In compounds of formula (4) where R5 and R6 are different, making the carbon to which they are attached a chiral centre, reaction of a nucleophile such as a Grignard reagent, an alkyl or aryl lithium reagent or a hydride reducing agent may lead to compounds of formula (3) where one of the two possible stereochemical configurations at the chiral centre to which R2 is attached, is formed selectively. In favourable cases, such as the addition of hydride reducing agents, it may be possible to selectively prepare compounds of formula (3) with a specific stereochemical configuration at the carbon to which R2 is attached. In such cases suitable hydride reducing agents may be, for example DIBAL which may give a compound of formula (3) with a specific configuration at the carbon to which R2 is attached, or alternatively K-selectride which may give a compound of formula (3) with the opposite configuration at the carbon to which R2 is attached. In such cases the absolute configuration of the carbon to which R2 is attached in the compound of formula (3) will also be determined by the absolute configuration of the carbon to which R5 and R6 are attached. In such cases it may be a possible to selectively synthesise all four of the possible diastereoisomers of a compound of formula (3) where the carbon to which R2 is attached and the carbon to which R5 and R6 are attached are both chiral centres.
Compounds of formula (3) may also be prepared directly from compounds of formula (5), initially by metallation using a suitable metallating agent such as BuLi, followed by addition of a suitably N-protected xcex1-aminoketone or aldehyde such as a compound of formula (19) where R2, R3, R5 and R6 are as defined above. 
In such cases the absolute configuration of the carbon to which R2 is attached in a compound of formula (3) will be determined by the absolute configuration of the carbon to which R5 and R6 are attached in the compound of formula (19). In favourable cases it may be possible to selectively synthesise specific diastereoisomers of a compound of formula (3) by use of an aldehyde or ketone of formula (19) with a specific absolute configuration at the carbon to which R5 and R6 are attached.
Compounds of formula (4) where R3 is alkyl are synthesised by standard methods from compounds of formula (4) where R3 is hydrogen for example by alkylation with a suitable alkyl halide in the presence of a base such as NaH. Compounds of formula (4) are synthesised from compounds of formula (5) by standard methods such as initial metallation by using a suitable metallating agent such as BuLi, followed by addition of a suitably N-protected xcex1-amino acid derivative such as an ester, lactone, acid chloride, acid anhydride, amide or N,O-dialkylhydroxarnic acid derivative.
Compounds of formula (I) where R3 or R4 are COR13, CO2R13, CONR13R14 or SO2R13 may be prepared from compounds of formula (1) where R3 or R4 are hydrogen by standard literature methods such as treatment with an acid chloride (R13COCl), chloroformate (ClCO2R13), isocyanate (R13NCO), chloroformamide (ClCONR13R14) or sulphonyl chloride (ClSO2R13). Compounds of formula (1) where R3 or R4 are CONR13NR14R15 may be prepared from compounds of formula (1) where either R3 or R4 are hydrogen by standard literature methods such as treatment with phosgene at low temperature followed by treatment with a suitable substituted hydrazine derivative (HNR13NR14R15).
Compounds of formula (2) where R3 and R4 are hydrogen, alkyl or aryl and R2 is hydrogen are synthesised from compounds of formula (6) (Reaction Scheme 2) by reaction with a suitable reducing agent such as NaBH4. Compounds of formula (2) where R3 and R4 are hydrogen, alkyl or aryl and R2 is alkyl or aryl are synthesised from compounds of formula (6) by reaction with a suitable nucleophile such as a Grignard reagent or alkyl or aryl lithium reagent. Compounds of formula (6) where R3 and R4 are hydrogen, alkyl or aryl are synthesised from compounds of formula (7) by standard literature methods such as treatment with a suitably substituted alkyl or aryl amine derivative (HNR3R4). 
Compounds of formula (8) (Reaction Scheme 3), where n is 1 are synthesised from compounds of formula (2) by standard literature methods such as treatment with phosgene or carbonyl diimidazole. Compounds of formula (8) where n is 0 are synthesised from compounds of formula (2) by standard literature methods such as treatment with formaldehyde.
Compounds of formula (9) are synthesised from compounds of formula (10) by standard literature methods such as reduction with a suitable reducing agent such as borane. Compounds of formula (10) are synthesised from compounds of formula (2) by standard literature methods such as treatment with a suitable xcex1-halo acid halide such as chloroacetyl chloride in the presence of a suitable base such as NaOH. The use of a suitably substituted xcex1-halo acid halide would lead to a compound of formula (11) which is additionally substituted in the azapyran ring.
Compounds of formula (2) where R2, R5 and R6 are hydrogen are synthesised from compounds of formula (11) by standard literature methods such as treatment with a suitably substituted amine (HNR3R4). 
Compounds of formula (2) where R3 and R4 are both hydrogen are prepared from compounds of formula (12) (Reaction Scheme 4) in two steps by standard methods such as initial treatment with a suitable nitro compound (R5R6CHNO2) in the presence of a suitable base such as Amberlyst 21, followed by reduction of the intermediate nitro compound with a suitable reducing agent such as zinc in acetic acid. 
Compounds of formula (7) are known in the literature or are prepared from ketones of formula (14) (Reaction Scheme 5) by standard literature methods such as by xcex1-bromination of the ketone using a suitable brominating agent, followed by treatment with NaOMe. Compounds of formula (14) are known in the literature or are prepared from bromoquinolines of formula (5) by standard literature methods such as by initial metallation with a suitable metallating agent such as BuLi, followed by addition of a suitably activated carboxylic acid derivative such as an ester, lactone, acid chloride, acid anhydride, amide or an N,O-dialkylhydroxamic acid derivative.
Compounds of formula (13), including compounds of formula (11), are known in the literature or are prepared from compounds of formula (14) by standard literature methods such as initial xcex1-bromination using a suitable brominating agent, followed by treatment with a suitable reducing agent such as NaBH4.
Compounds of formula (12) are known in the literature or are synthesised from compounds of formula (5) by standard literature methods such as by initial metallation with a suitable metallating agent such as BuLi, followed by addition of a suitably activated carboxylic acid derivative such as an ester, lactone, acid chloride, acid anhydride, amide or an N,O-dialkylhydroxamic acid derivative.
Compounds of formula (5) are known in the literature or are prepared from compounds of formula (15) by standard methods such as treatment with POBr3. Compounds of formula (5) where R7 is bromine are known in the literature or are prepared directly from anilines of formula (16) by treatment with, for example malonic acid or a suitably substituted malonic acid derivative in the presence of POBr3. 4-Bromoquinolines (5) where R7 is bromine may also be prepared from 4-hydroxyquinolines (15) where R7 is hydroxy, by treatment with POBr3. 4-Hydroxyquinolines (15) are either known in the literature or are prepared from anilines (16) by standard literature methods such as reaction with a suitably substituted acetoacetate ester derivative in the presence of a suitable acid catalyst or dehydrating agent such as polyphosphoric acid. Anilines (16) are commercially available, are known in the literature or may be prepared by standard literature methods. 
Synthetic preparation of some of the compounds of formula (I) where R1-R12 are as defined above, may require the use of protecting groups to avoid certain functional groups interfering in the normal course of a reaction. The protecting groups used in the preparation of the compounds of formula (I) are selected from a range of protecting groups commonly used in organic synthesis. This may include, for example the protection of amines with benzyl, substituted benzyl, diphenylmethyl or butoxycarbonyl groups or as a nitro group, the protection of alcohols with, for example benzyl, substituted benzyl, t-butyl or trialkylsilyl groups, and the protection of ketones as ketals or thioketals. In all cases deprotection of these functional groups is carried out by standard literature procedures known to those skilled in the art.
The invention further relates to the compounds disclosed herein.
According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
The pharmaceutical compositions employed in the present invention comprise a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and may also contain other therapeutic ingredients known to those skilled in the art.
Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of formula (I). For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The most suitable route in any given case will depend on the severity of the condition being treated. The most preferred route of administration of the present invention is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practical use, the compounds of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.
Pharmaceutical compositions employed in the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.